Summary
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Multipotent versus restricted
Morphologically detectable neural crest cells usually are first observed as the cells individualize and delaminate upon emigration from the neural tube, following their epithelial to mesenchymal transition (EMT), in which they convert from a tightly adherent sheet of cells to a dispersed and more individual mesenchymal population. Prior to EMT, however, it is difficult or impossible at most axial levels and in most species to distinguish presumptive neural crest cells from cells that will form dorsal neural tube derivatives. However, there are exceptions, such as a subpopulation of cranial neural crest cells in chick and mouse that appears to be set aside and morphologically distinct at midbrain levels. In addition, some species such as axolotl have a clearly segregated population of neural crest cells that exists as a ridge on the dorsal neural tube.
A long-standing debate in the neural crest literature has been whether neural crest cells are multipotent and/or restricted in their developmental potential. In other words, can a single neural crest precursor form only one type of derivative or are the cells multipotent and able to produce multiple derivatives. Single cell lineage experiments (Bronner-Fraser and Fraser, 1988), in which individual cells within the chick dorsal neural tube are labeled with vital dye, show that some of the labeled clones contribute to multiple differentiated cell types in the periphery, including melanocytes, sympathetic and sensory ganglion cells. Thus, the original precursor was âmultipotentâ in its developmental potential to form neural crest derivatives. In addition to neural crest derivatives, single dorsal neuroepithelial cell also give rise both to migrating neural crest cells and cells that remain in the dorsal neural tube, such as roof plate cells and dorsal sensory neurons and/or interneurons. This suggests a shared lineage between the neural tube and neural crest, at least at this stage. However, labeling migrating neural crest cells in vivo also produced clones that could contribute to more than one neural crest lineage (Fraser and Bronner-Fraser, 1991), again supporting the idea that some of the migrating population retained multipotency.
Clonogenic culture of neural crest cells cultured shortly after their emigration from the neural tube definitely shows that many early migrating neural crest cells are multipotent in vitro as well (Baroffio et al., 1988, Calloni et al., 2007, Calloni et al., 2009, LeDouarin et al., 2008a, LeDouarin et al., 2008b, Sieber-Blum and Cohen, 1980 and Stemple and Anderson, 1993). Exposure to different growth factors can profoundly influence their lineage decisions (e.g. Lahav et al., 1998). Furthermore, they have a capacity for self-renewal, at least for a few cell divisions (Stemple and Anderson, 1993 and Trentin et al., 2004).
The fact that individual neural crest cells can form multiple derivatives has led to the idea that they have stem cell properties. Stem cells are defined as individual progenitor cells that can generate one or more specialized cell types. A cardinal feature of stem cells is their ability to self-renew, that is, to divide so as to give rise to at least one daughter cell that maintains the multipotent character of its parent. The fact that cloned neural crest cells have a limited ability to self-renew has led to the idea that they are stem-like (progenitors) cells rather than true stem cells. Interestingly, however, neural crest stem cells can be derived from adult tissues (Fernandes et al., 2008 and Shakhova and Sommer, 2010; see Chapter Dupin and Sommer), suggesting that they can remain quiescent for long periods of time or maintain long term self-renewal ability when left in situ.
The presence of some multipotent neural crest precursors cannot, however, rule out the possibility that other precursors may be more restricted in their developmental potential. In fact, experiments in zebrafish suggested that neural crest cells contribute to different sets of derivatives accordingly to their migration order (Raible and Eisen, 1994). However, if the leader cell was ablated, the next cell in line took up the fate that would have been filled by the ablated cell (Raible and Eisen, 1996). Similarly, early migrating neural crest cells normally exhibit a broader range of derivatives than later migrating cells; however, when the early population is ablated and replaced by late migrating cells, the late migrating cells assume a broader developmental potential than that prescribed by their normal fate (Baker et al., 1997). This raises a very important issue: that developmental potential is greater than or equal to a cell's normal fate. Only by challenging the cell by putting it into a new environment can one test for restriction of cell fate. This is best exemplified by experiments in which the potential of neural crest populations was challenged by performing heterotopic transplants between different axial levels (LeDouarin and Teillet, 1974), such as exchanging cranial and trunk, or vagal and trunk populations. The results demonstrate a combination of flexibility in cell fate and some axial level-autonomous characteristics. For example, cranial neural crest cells normally make cartilage and bone of the face whereas trunk neural crest cells do not. Transplantation of cranial neural folds to the trunk results in production of many normal trunk derivatives, as well as the formation of ectopic cartilage nodules (Le Lievre et al., 1980 and LeDouarin and Teillet, 1974). Conversely, transplantation of trunk neural folds to the head results in contributions to cranial neurons and glia of cranial ganglia, but not to cartilage, although some connective tissues and pericytes derive from this graft (Nakamura and Ayer-le Lievre, 1982). This reveals some flexibility in fate, but a more limited ability to form skeletal derivatives (LeDouarin et al., 2004). However, trunk neural crest cells can form cartilage in vitro under appropriate culture conditions (Calloni et al., 2007 and McGonnell and Graham, 2002). Because challenging prospective neural crest fate is a difficult experiment, it is much easier to prove multipotency than restricted cell fate, leaving the question of whether or not there are lineage-restricted neural crest precursors still open to debate (see Krispin et al., 2010).
